This study will test a proposition that environmental toxins are involved in the cause of Sporadic AIzheimer's disease (AD) by inducing, early in life, a less resilient but functional set of Nucleus Basalis of Meynert (NBM) acetylcholinergic (Ach) neurons that cannot withstand the stress placed on them later in life. Two stages of afflictions, therefore, are involved. The 1st is a predisposing or sensitizing stage that occurs early in life, causes mostly epigenetic changes that impair the phenotype and/or reduce the number of the NBM Ach neurons. The 2nd superimposing/precipitating stage occurs when age-related wear-and-tear or other interventions damage the already susceptible NBM neurons and precipitate AD. The project will identify interventions that will mimic the two stages. The plant-derived tubulin assembling inhibitors, colchicines; the fungal-derived protein synthesis inhibitor, puromycin, and the fungal and plants-derived mitochondrial toxin, 3-nitroproprionic acid (3-NP) will be administered during the period of differentiation of the NBM Ach neurons of the embryos in timed-pregnant mice to induce the 1st stage. Age-related studies will verify the trans-placental or indirect in utero changes related to memory functions and the anatomy and histochemistry of the NBM Ach neurons, thus testing the vulnerability of the neurons to the wear-and-tear of life. The anticholinergic agent, scopolamine, that causes amnesia will be used, also, to mimic the 2nd stage and rationally to precipitate Alzheimer's disease-like changes in the pups. It is proposed that the ED50 for the induction of amnesia will be lower in the 1st stage treated mice, as compare to control. A new model for AD may be identified, based on chemically producing a less resilient but functional NBM Ach neuronal phenotype early in life and stressing those susceptible neurons later in life. Interventions that prevent or delay the toxic responses will be tested. This concept is relevant to the role of the environmental in about 90% of AD cases, and it may be used to study other neurodegenerative disorders but focusing on other neuronal sets. The mechanisms that underlie the proposed sensitization and precipitating stages, such as DNA and RNA editing and protein modifications, will be studied in the future.